Evidence for Multiple Binding Modes in the Initial Contact Between SARS‐CoV‐2 Spike S1 Protein and Cell Surface Glycans

Infection of host cells by SARS‐CoV‐2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate (HS), tethering the virus to the extracellular matrix environment, and causing the subunit S1‐RBD to undergo a conformational change into the ‘open’ conformation. These two ev...

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Vydané v:	Chemistry : a European journal Ročník 29; číslo 1; s. e202202599 - n/a
Hlavní autori:	Parafioriti, Michela, Ni, Minghong, Petitou, Maurice, Mycroft‐West, Courtney J., Rudd, Timothy R., Gandhi, Neha S., Ferro, Vito, Turnbull, Jeremy E., Lima, Marcelo A., Skidmore, Mark A., Fernig, David G., Yates, Edwin A., Bisio, Antonella, Guerrini, Marco, Elli, Stefano
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Germany Wiley Subscription Services, Inc 02.01.2023 John Wiley and Sons Inc
Predmet:	ACE2 Angiotensin Angiotensin-converting enzyme 2 Binding Binding Sites Cell fusion Cell membranes Cell surface Chemistry COVID-19 Extracellular matrix Heparan sulfate Humans Magnetic resonance spectroscopy MD simulation Membrane fusion Molecular dynamics Molecular Dynamics Simulation NMR NMR spectroscopy Nuclear magnetic resonance Oligosaccharides Peptidyl-dipeptidase A Polysaccharides Protein Binding Protein Domains Protein S protein S spike Proteins SARS-CoV-2 SARS-CoV-2 - metabolism Severe acute respiratory syndrome Severe acute respiratory syndrome coronavirus 2 Spike Glycoprotein, Coronavirus - chemistry Tethering Viral diseases Viruses MD simulation SARS-CoV-2 heparan sulfate NMR spectroscopy protein S spike
ISSN:	0947-6539, 1521-3765, 1521-3765
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Shrnutí:	Infection of host cells by SARS‐CoV‐2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate (HS), tethering the virus to the extracellular matrix environment, and causing the subunit S1‐RBD to undergo a conformational change into the ‘open’ conformation. These two events promote the binding of S1‐RBD to the angiotensin converting enzyme 2 (ACE2) receptor, a preliminary step toward viral‐cell membrane fusion. Combining ligand‐based NMR spectroscopy with molecular dynamics, oligosaccharide analogues were used to explore the interactions between S1‐RBD of SARS CoV‐2 and HS, revealing several low‐specificity binding modes and previously unidentified potential sites for the binding of extended HS polysaccharide chains. The evidence for multiple binding modes also suggest that highly specific inhibitors will not be optimal against protein S but, rather, diverse HS‐based structures, characterized by high affinity and including multi‐valent compounds, may be required. More than one way to get in: A hexasaccharide bound to site I of the spike protein in two binding modes (orange and green tubes) shows that multiple binding modes between heparan sulfate (HS) and S1 (electrostatic potential map on the surface) are allowed. The hypothetical macromolecular complex HS−S1 does not interfere with the interaction involving S1‐RBD and ACE2, thus supporting the co‐receptor role of HS in the activation of the SARS‐CoV‐2 S protein.
Bibliografia:	A previous version of this manuscript has been deposited on a preprint server (https://doi.org/ doi: 10.26434/chemrxiv‐2022‐21brb‐v2) ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0947-6539 1521-3765 1521-3765
DOI:	10.1002/chem.202202599